ALK gene alteration is one of the molecular biomarkers for treatment of non-small cell lung cancer (NSCLC). First- and second-generation ALK tyrosine kinase inhibitor (TKI) is approved for ALK-positive non–small-cell lung cancer. However, the development of ALK mutations is one of drug resistance mechanism after receiving ALK TKI treatment. In a phase II clinical trial, ALK-positive NSCLC patients with prior first- and second-generation ALK TKI treatment were treated with lorlatinib, an FDA-approved third-generation ALK TKI. The plasma or tissue from patients was analyzed with a genetic test for the detection of ALK mutations. Patients with ALK mutations were detected in 24% (45/189) and 24% (40/164) of plasma and tissue respectively. In patients with first-generation ALK TKI-pretreated, lorlatinib showed comparable efficacy among patients with and without ALK mutations. In patients with second-generation ALK TKI-pretreated, lorlatinib showed more efficiency in patients with ALK mutations than patients without ALK mutations (62% v.s. 32% [plasma]; 69% v.s. 27% [tissue]). The progression-free survival didn't show a significant difference in patients with or without ALK mutations identified by plasma genetic test. Interestingly, in patients with ALK mutation identified by tissue genetic test, the progression-free survival was 11.0 months in patients with ALK mutations, and 5.4 months in patients without ALK mutations (hazard ratio, 0.47). The results revealed the efficacy of lorlatinib in ALK mutation-positive NSCLC patients who have failed prior ALK inhibitor. Furthermore, the ALK mutations identified by tissue genotype can predict the potential clinical benefits of lorlatinib.
Shaw AT, et al. J Clin Oncol. 2019